Denosumab for the Treatment of Smoldering Multiple Myeloma: Rates of Osteoporosis and Change in Lowest T-Score after 12 Months of Treatment

Background: Smoldering multiple myeloma (SMM) is a plasma cell precursor disease state with variable risk of progression to symptomatic multiple myeloma (MM). The standard of care for the treatment of SMM remains observation. Numerous clinical trials have sought to determine optimal treatment options for SMM but have either failed to demonstrate clinical efficacy, or resulted in unacceptable toxicity for the treatment of a disease that may not lead to progression in a select group of patients. Denosumab is a human monoclonal IgG2 antibody directed against RANKL, that has demonstrated non-inferiority to zoledronic acid for the prevention of lytic bone lesions in MM patients. We are investigating the use of denosumab in patients with SMM and hypothesize that it will lead to decreased rates of progression to symptomatic myeloma and increased bone mineral density. In this report, we describe the rates of osteoporosis and change in T-scores for patients that have received all 12 planned treatment doses on study.

Methods: This is a single-center, open-label, phase II single-arm trial of denosumab in patients with smoldering multiple myeloma, with at least 1 high-risk feature for progression. All patients will receive denosumab 120 mg administered by subcutaneous injection every 4 weeks for a total of 12 cycles. Patients underwent bone mineral density analysis by dual-energy X-ray absorptiometry (DEXA) scan at the time of enrollment and after completing study treatment at 13 months.

Results: At the time of analysis, target enrollment of 20 patients has been reached with a median age of 73 (38-82), 55% of participants being male and 90% identifying as Caucasian/white. At enrollment, 15% of patients were classified as osteoporotic and 40% were classified as osteopenic. Of the 12/20 (60%) of patients that have completed all 12 doses of denosumab, 9 had an increase or no change in their lowest t-score [75%, 95% CI=(42.8, 94.5%)]. Only 1 of 12 patients that completed all doses changed classification from osteoporotic to osteopenic. Of the 8 patients that have not completed all 12 doses of denosumab, 3 are still receiving treatment, 3 stopped treatment due to biochemical progression of disease, and 2 patients withdrew from study. One patient withdrew due to COVID-19 concerns and another patient withdrew due to extensive dental work that was required during the treatment period. None of the patients have had a response to treatment and 6/20 (30%) have progressed. Three of those patients progressed while on treatment and 3 patients progressed after completing study treatment. All progression of disease has been biochemical and there have been no skeletal-related events recorded at the time of this report.

Conclusion: While there appears to be minimal disease response of SMM to denosumab, there does appear to be either stable or increased bone mineral density in the majority of patients that have completed therapy thus far. All patients that have progressed since initiation of the study experienced biochemical progression and no patients have had skeletal-related events at the time of this report.

Acknowledgments: Amgen provided financial support and drug for conduction of this clinical trial. We thank our patients for participating in this clinical trial.

Lipe:Janssen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Sanofi: Consultancy; GSK: Consultancy; Seagen Inc.: Research Funding; Amgen: Research Funding; Harpoon: Research Funding.